Potential role and therapeutic implications of glutathione peroxidase 4 in the treatment of Alzheimer's disease

作     者：Yanxin Shen Guimei Zhang Chunxiao Wei Panpan Zhao Yongchun Wang Mingxi Li Li Sun Yanxin Shen;Guimei Zhang;Chunxiao Wei;Panpan Zhao;Yongchun Wang;Mingxi Li;Li Sun

作者机构：Department of Neurology and Neuroscience CenterThe First Hospital of Jilin UniversityJilin UniversityChangchunJilin ProvinceChina Cognitive Impairment CenterDepartment of NeurologyThe First Hospital of Jilin UniversityJilin UniversityChangchunJilin ProvinceChina 

出 版 物：《Neural Regeneration Research》 (中国神经再生研究（英文版）)

年 卷 期：2025年第20卷第3期

页      面：613-631页

核心收录：

学科分类：1002[医学-临床医学] 100203[医学-老年医学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China,No.82071442 (to LS) a grant from the Jilin Provincial Department of Finance,No.JLSWSRCZX2021-004 (to LS) 

主　　题：apoptosis ferroptosis inflammation lipid peroxidation natural plant products neurodegenerative disorder neuroprotection oxidative stress small-molecule drugs 

摘      要：Alzheimer s disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer s disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer s disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer s disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer s disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer s disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer s disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer s disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer s disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer s disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinica